Safety & Transparency Shape Drug Development

An important component in protecting public health, says Margaret Hamburg, new commissioner of the Food and Drug Administration, is to assure access to innovative, safe, and effective medical products.

Jill Wechsler

Achieving the agency's fundamental goals of promoting health, preventing illness, and prolonging life cannot be measured in the number of facilities inspected or drugs approved, Hamburg and Principal Deputy Commissioner Joshua Sharfstein stated in an online editorial in the New England Journal of Medicine (May 26, 2009). Success involves developing needed vaccines, preventing safety problems, and pursuing opportunities to advance science.

In facilitating access to needed medicines, FDA's new leaders recognize the need to balance the benefits of medical products against potential harm based on consideration of severity of illness at issue, availability of alternative treatments, and the state of knowledge about individual responses. Such calculations may lead to added restrictions on the use of new medications at the time of approval while sponsors gather additional safety data on long-term safety and efficacy.

The FDA Amendments Act of 2007 (FDAAA) supports this quest by giving FDA several new tools for ensuring drug safety through the entire product life cycle. These include authority to require postapproval label changes when new safety issues arise and to crack down on manufacturers that fail to conduct agreed-on postmarketing studies.

FDAAA also requires more extensive listing of clinical trials and study results on the ClinicalTrials.gov public Web site, partly to ensure that safety issues arising during clinical research are fully disclosed to regulatory authorities and to the public. And the measure expands FDA's options for limiting patient access to newly approved drugs that raise safety concerns through the Risk Evaluation and Mitigation Strategies (REMS) program.

Expanding REMS

Under FDAAA, a REMS may consist of just a Medication Guide and a timetable for evaluation 18 months, three years, and seven years following approval. More elaborate REMS programs may require a communication plan for conveying safety information to prescribers, pharmacists, and patients.

The most high-risk drugs also have to establish Elements to Assure Safe Use, which can include special training or certification of health professionals; limited distribution to ensure that a drug is dispensed only to patients who meet certain criteria; patient monitoring to identify adverse reactions; and enrollment of patients in registries for long-term oversight. Over the past 18 months, FDA has approved REMS for some 50 products—drugs and medical products already on the market as well as new treatments.

The ability of the REMS program to keep high-risk products on the market by limiting inappropriate access faces an important test in a new FDA initiative to establish a massive safety program for the entire class of extended-relief opioid medicines. This covers 24 brand and generic products, such as fentanyl patches and oral drugs formulated with oxycodone, hydromorphone, methadone, morphine, and oxymorphone.

The aim is to ensure continued access to medications essential for patients suffering from chronic pain while also curbing inappropriate prescribing, unintentional overdosing, and intentional abuse. Some 23 million prescriptions of these painkillers are dispensed annually to about 4 million patients in the United States, even though long-acting opioids can cause respiratory distress if prescribed to inappropriate patients or in too-high doses. These drugs also are open to abuse because they can be crushed or dissolved to permit a large dose to be taken at once. Some 12 million Americans over the age of 12 took pain relievers for nonmedical use in 2007.

Federal officials really do not want to pull these products off the market because opioids are important for managing chronic severe pain in many individuals. The hope is to improve prescribing through more coordinated risk management strategies that better inform patients about the serious dangers associated with these drugs, to expand training for health professionals as to proper prescribing, and to improve tracking and surveillance of how the drugs are used.

FDA held an open public meeting in May to discuss such strategies. More than 70 speakers presented opinions to a panel headed by Douglas Throckmorton, deputy director of the Center for Drug Evaluation and Research (CDER), and John Jenkins, director of CDER's Office of New Drugs.

Parents of teens who died from OxyContin overdoses demanded that FDA remove these drugs from the market. Representatives of the pain community stressed the need for access to these medicines and warned that restricted distribution systems and complex oversight programs could be harmful to patients and costly to the health care system.

The opioid class REMS is unique in that it requires brand and generic manufacturers to jointly devise a single shared system to monitor safety and risk of dozens of products, a tricky task for fierce competitors.

Pharmacists and providers want uniform education and certification programs that fit current work flows and the existing DEA (Drug Enforcement Agency) registration system. Manufacturers don't want to run the whole program and seek strong participation by prescribers and dispensers, as well as the DEA, state licensing boards, and other parties.

While FDA digests these proposals and develops a REMS proposal for advisory committee consideration later this year, agency officials say they won't hold up the review and approval of new opioid products in the pipeline. Purdue Pharma is seeking FDA approval of a new oxycodone product, but has run into trouble documenting whether the drug really will deter abuse. King Pharmaceuticals awaits agency approval of two new formulations with anti-abuse claims.

Once FDA issues a REMS proposal for these drugs, which could take a year or more, it will be up to each manufacturer to file an implementation plan and carry it out. Success with the opioid REMS may encourage additional postapproval control and educational programs for other widely prescribed drugs. FDA is working on a REMS for erythropoiesis-stimulating agents (ESAs), and a similar initiative is likely for botulinum toxin products.

In recent years, FDA has requested stronger label warnings for COX-2 inhibitors, antidepressants, and antiepileptics; more comprehensive REMS programs may be on the horizon.

More disclosure

FDA officials emphasize the importance of transparency in developing a program to ensure safe use of opioids, a strategy that Hamburg and Sharfstein consider very important for boosting FDA's credibility. To that end, FDA has formed a high-level transparency task force to identify ways to better inform the public about its operations and decisions.

As part of the Obama administration's campaign for more open government, FDA's transparency initiative aims to identify information on regulated products and on agency activities that could be made public.

This exercise promises to raise questions about why certain industry information on drug products is kept secret. At the top of the list is clinical trial data and drug safety information traditionally considered confidential. Disclosure advocates believe that such protection may hide important information on drug risks and adverse events. And even though more clinical trial information is being posted on the ClinicalTrials.gov Web site, the critics say that such summary data is not enough.

The panel is headed by Sharfstein and includes Chief Scientist Jesse Goodman, Acting Chief Counsel Michael Landa, and the leaders of all FDA centers and its field force.

Sharfstein acknowledges that some proprietary information probably should remain confidential, such as the formula for making a certain pill, and that concerns about patient privacy and other issues may limit full data transparency. But the initiative opens the door to broader disclosure of sponsors' private records. Unpublished clinical and preclinical studies, product formulations, and manufacturing data have long been considered trade secrets, and pharma companies are likely to mount a stiff defense of the rules and laws that protect their rights.

FDA may have more leeway to expand transparency about its own decisions and regulatory actions. The agency currently announces product approvals, but not when it turns down an application. And it's up to sponsors to disclose when they file an application or withdraw a submission. Hamburg told reporters that she wants to address complaints that FDA is a "block box" by clarifying agency processes. In many cases there may be a good explanation for an agency decision, and it would help to release information that reduces confusion and criticism.

FDA began its transparency review with a public meeting last month. Hamburg expects a report by year-end on what additional information the agency can release on its own and what changes require new regulations or Congressional action.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com